We propose to investigate the pathophysiology of choroidal degeneration in age-related macular degeneration (AMD), the most common form of untreatable central vision loss in the western world. The choroid, the complex vascular system supplying the outer retina, photoreceptors, and retinal pigment epithelium (RPE), can now be visualized in living humans using enhanced depth imaging optical coherence tomography (OCT). Recent studies of the choroid by clinicians using OCT, and by laboratory scientists using donor eyes, suggest the choroid is a critical tissue in the pathogenesis AMD, especially as it relates to degeneration of the RPE in geographic atrophy. Access to patients with AMD (from Iowa and from large, multicenter eye studies), a large human donor eye collection, extensive experience in histology, molecular biology, genetics, and image processing/analysis, and state-of-the-art genetics and molecular biology laboratories will provide us with a unique opportunity to uncover the critical role of the choroid in AMD. We will use human donor eyes to determine the biochemical pathways and anatomical differences occurring in eyes with AMD. This will allow us to explore the anatomic details of choroidal loss and determine the molecular basis of changes in thin choroids and eyes with AMD. We will also explore the consequences of choroidal loss on the retina in novel animal models. Finally, we will leverage our extensive experience in genetics to evaluate the extent to which genes already implicated in AMD also form the basis for choroidal degeneration using very large patient cohorts. This project also has the prospect of discovering new genes that impact structural features of the choroid and AMD biology. Our experiments will lead to a better understanding of this blinding disease and pave the way for treatments that can be utilized for patients with AMD.